rs75568433

Variant names:

• chr14-64130105-C-A
• rs75568433
• NM_182914.3:c.14197C>A

Your query was ambiguous. Multiple possible variants found:

• chr14-64130105-C-A
• chr14-64130105-C-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_182914.3(SYNE2):​c.14197C>A​(p.Pro4733Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0149 in 1,614,150 control chromosomes in the GnomAD database, including 227 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P4733R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.010 (8 hom., cov: 32)
  • Exomes 𝑓: 0.015 (219 hom.)
• Consequence: SYNE2 NM_182914.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.78
• Publications: 12 publications found

Genes affected

SYNE2 (HGNC:17084): (spectrin repeat containing nuclear envelope protein 2) The protein encoded by this gene is a nuclear outer membrane protein that binds cytoplasmic F-actin. This binding tethers the nucleus to the cytoskeleton and aids in the maintenance of the structural integrity of the nucleus. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2009]

ESR2 (HGNC:3468): (estrogen receptor 2) This gene encodes a member of the family of estrogen receptors and superfamily of nuclear receptor transcription factors. The gene product contains an N-terminal DNA binding domain and C-terminal ligand binding domain and is localized to the nucleus, cytoplasm, and mitochondria. Upon binding to 17beta-estradiol or related ligands, the encoded protein forms homo- or hetero-dimers that interact with specific DNA sequences to activate transcription. Some isoforms dominantly inhibit the activity of other estrogen receptor family members. Several alternatively spliced transcript variants of this gene have been described, but the full-length nature of some of these variants has not been fully characterized. [provided by RefSeq, Jul 2008]

ESR2 Gene-Disease associations (from GenCC):

• male infertility with azoospermia or oligozoospermia due to single gene mutation

  Inheritance: AR Classification: MODERATE Submitted by: King Faisal Specialist Hospital and Research Center
• familial medullary thyroid carcinoma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• ovarian dysgenesis 8

  Inheritance: AD, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005111128).
• BP6: Variant 14-64130105-C-A is Benign according to our data. Variant chr14-64130105-C-A is described in ClinVar as Benign. ClinVar VariationId is 313597.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0102 (1552/152306) while in subpopulation NFE AF = 0.0172 (1168/68024). AF 95% confidence interval is 0.0164. There are 8 homozygotes in GnomAd4. There are 699 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1552 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_182914.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNE2	NM_182914.3	MANE Select	c.14197C>A	p.Pro4733Thr	missense	Exon 76 of 116	NP_878918.2	Q8WXH0-2
	SYNE2	NM_015180.6		c.14197C>A	p.Pro4733Thr	missense	Exon 76 of 115	NP_055995.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNE2	ENST00000555002.6	TSL:1 MANE Select	c.14197C>A	p.Pro4733Thr	missense	Exon 76 of 116	ENSP00000450831.2	Q8WXH0-2
	SYNE2	ENST00000344113.8	TSL:1	c.14197C>A	p.Pro4733Thr	missense	Exon 76 of 115	ENSP00000341781.4	Q8WXH0-1
	SYNE2	ENST00000394768.6	TSL:1	n.3730C>A		non_coding_transcript_exon	Exon 24 of 63

Frequencies

GnomAD3 genomes AF: 0.0102 AC: 1555 AN: 152188 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.00314

Gnomad AMI AF: 0.0208

Gnomad AMR AF: 0.00739

Gnomad ASJ AF: 0.0167

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000830

Gnomad FIN AF: 0.00330

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0172

Gnomad OTH AF: 0.0124

GnomAD2 exomes AF: 0.00975 AC: 2446 AN: 250990 AF XY: 0.00945

Gnomad AFR exome AF: 0.00265

Gnomad AMR exome AF: 0.00581

Gnomad ASJ exome AF: 0.0180

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00407

Gnomad NFE exome AF: 0.0158

Gnomad OTH exome AF: 0.0116

GnomAD4 exome AF: 0.0154 AC: 22445 AN: 1461844 Hom.: 219 Cov.: 32 AF XY: 0.0150 AC XY: 10907 AN XY: 727222

African (AFR) AF: 0.00242 AC: 81 AN: 33480

American (AMR) AF: 0.00624 AC: 279 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0164 AC: 428 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00211 AC: 182 AN: 86254

European-Finnish (FIN) AF: 0.00446 AC: 238 AN: 53418

Middle Eastern (MID) AF: 0.00192 AC: 11 AN: 5740

European-Non Finnish (NFE) AF: 0.0184 AC: 20423 AN: 1112004

Other (OTH) AF: 0.0133 AC: 803 AN: 60392

GnomAD4 genome AF: 0.0102 AC: 1552 AN: 152306 Hom.: 8 Cov.: 32 AF XY: 0.00939 AC XY: 699 AN XY: 74474

African (AFR) AF: 0.00308 AC: 128 AN: 41564

American (AMR) AF: 0.00738 AC: 113 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0167 AC: 58 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.000623 AC: 3 AN: 4818

European-Finnish (FIN) AF: 0.00330 AC: 35 AN: 10616

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0172 AC: 1168 AN: 68024

Other (OTH) AF: 0.0123 AC: 26 AN: 2116

Alfa AF: 0.0147 Hom.: 58

Bravo AF: 0.0106

TwinsUK AF: 0.0170 AC: 63

ALSPAC AF: 0.0215 AC: 83

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.0198 AC: 170

ExAC AF: 0.00966 AC: 1173

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.0141

EpiControl AF: 0.0167

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Emery-Dreifuss muscular dystrophy 5, autosomal dominant (2)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.090
CADD	Benign	20
DANN	Benign	0.73
DEOGEN2	Benign	0.029	T
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.92	D
MetaRNN	Benign	0.0051	T
MetaSVM	Benign	-0.75	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		1.8
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.15
Sift	Benign	0.11	T
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.61
MVP		0.51
MPC		0.34
ClinPred		0.022	T
GERP RS		5.8
Varity_R		0.14
gMVP		0.15
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs75568433; hg19: chr14-64596823; COSMIC: COSV100648735;